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Fc-saxatilin suppresses hypoxia-induced vascular leakage by regulating endothelial occludin expression

 H.-J. Choi  ;  I. Kwon  ;  N.-E. Kim  ;  J. Kim  ;  S. An  ;  S. Kang  ;  S.-Y. Hong  ;  H. S. Nam  ;  J. H. Heo 
 THROMBOSIS AND HAEMOSTASIS, Vol.117(3) : 595-605, 2017 
Journal Title
Issue Date
Animals ; Brain/blood supply* ; Capillary Permeability/drug effects* ; Cell Hypoxia ; Cell Line ; Disintegrins/pharmacology* ; Dose-Response Relationship, Drug ; Focal Adhesion Kinase 1/metabolism ; Human Umbilical Vein Endothelial Cells/drug effects* ; Human Umbilical Vein Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/pathology ; Humans ; Infarction, Middle Cerebral Artery/drug therapy* ; Infarction, Middle Cerebral Artery/metabolism ; Infarction, Middle Cerebral Artery/pathology ; Integrin alphaVbeta3/metabolism ; Ischemic Attack, Transient/drug therapy* ; Ischemic Attack, Transient/metabolism ; Ischemic Attack, Transient/pathology ; Male ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Mice ; Mice, Inbred ICR ; Microvessels/drug effects* ; Microvessels/metabolism ; Microvessels/pathology ; Occludin/metabolism* ; Phosphorylation ; Reperfusion Injury/metabolism ; Reperfusion Injury/pathology ; Reperfusion Injury/prevention & control* ; Signal Transduction/drug effects ; Time Factors
Fc-saxatilin ; disintegrin ; endothelial permeability ; occludin
Vascular leakage due to compromised integrity of the endothelial barrier is closely associated with brain damage in several neurological disorders, including ischaemic stroke. Saxatilin, a snake venom disintegrin containing the Arg-Gly-Asp (RGD) motif, exerts thrombolytic and antiplatelet effects by interacting with multiple integrins on platelets. Integrin signalling is indispensable for regulation of endothelial permeability. Saxatilin may play a role in vascular leakage after ischaemia because it has high affinity for endothelial integrins. Here, we determined whether Fc-saxatilin, an Fc-fusion protein of saxatilin, could prevent vascular leakage under hypoxic or ischaemic conditions. In mouse brain microvascular endothelial cells, hypoxia increased the permeability to FITC-dextran, and this effect was attenuated by Fc-saxatilin treatment. Fc-saxatilin also blocked vascular leakage of Evans Blue in the ischaemic brain induced by middle cerebral artery occlusion in mice. Furthermore, the expression of occludin, a tight junction protein, was reduced by hypoxia in endothelial cells. This downregulation of occludin was attenuated by Fc-saxatilin treatment. We also determined the activity of matrix metalloproteinases (MMPs) 2 and 9 because they are implicated in the degradation of occludin and of the microvascular basal lamina. Hypoxia increased MMP-9 activity, and this increase was attenuated by Fc-saxatilin treatment. Fc-saxatilin specifically bound to integrin αvβ3 of the endothelial cells and inhibited hypoxia-induced activation of FAK, a downstream signalling molecule in integrin-dependent signal transduction. Taken together, these results provide new insights into the mechanism via which Fc-saxatilin, as an integrin antagonist, prevents vascular leakage under ischemic conditions by regulating occludin expression in endothelial tight junctions.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Il(권일) ORCID logo https://orcid.org/0000-0001-9449-5646
Nam, Hyo Suk(남효석) ORCID logo https://orcid.org/0000-0002-4415-3995
Choi, Hyun-Jung(최현정) ORCID logo https://orcid.org/0000-0003-3695-3420
Heo, Ji Hoe(허지회) ORCID logo https://orcid.org/0000-0001-9898-3321
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